Radiation sterilization of hypercompressed polymer dosage forms

ABSTRACT

A sterile pharmaceutical dosage form which comprises an ester capped lactide polymer, glycolide polymer or a lactide-glycolide copolymer hypercompressed with an active pharmaceutical ingredient wherein said sterile pharmaceutical dosage form has been sterilized with an electron beam and a method of preparing said sterile pharmaceutical dosage form.

This application claims the priority of provisional application Ser. No.62/531,239, filed Jul. 11, 2017.

FIELD OF THE INVENTION

This invention relates to the field of sterilization of activepharmaceutical ingredients (API) dispersed in biologically compatiblepolymeric materials that have been hypercompressed (densified) to formcontrolled release pharmaceutical formulations.

BACKGROUND OF THE INVENTION

Hypercompressed (densified) biologically compatible lactide polymer,glycolactide or lactide-glycolactide copolymers containing APIs areknown. For many applications of these products, it is desirable toutilize radiation to sterilize these products prior to administration toor implantation in a patient. However, these hypercompressed polymers orcopolymers are susceptible to degradation when sterilized withradiation. When the API is a thermally unstable material such as apolypeptide or a protein, it is essential to use radiation forsterilization because those solid formulations may only be sterilized byradiation as production of these products in a sterile by process methodis not practicable. The applicant has observed that when gamma radiationis applied to make a sterile product based on a polymeric materialcomprising a lactide polymer, glycolactide or lactide-glycolactidecopolymer, these polymeric materials and any polypeptide or protein,which is present, may be degraded or denatured. This can result in aproduct where the API fails to meet regulatory standards for potency.

It is known that ionizing radiation interacts with the electrons ofpolymer molecules with a transfer of energy that results in ionformation and ejection of secondary electrons. Depending on the level ofkinetic energy of the secondary electrons, there can be furtherionization and excitation of other molecules present in the vicinity.The immediate outcome of the exposure to ionizing radiation, such asgamma radiation, is the formation of various energetic species such astrapped radicals, electrons and ions; the decays of these energeticspecies results in fragmentation and generates free radicals. Suchevents can both destabilize (chain scission) and stabilize(crosslinking) the polymeric material and or the API.

A significant factor affecting the interaction between the reactivespecies of degraded peptides and proteins is their proximity to eachother. Since hypercompression positions reactive species in closerproximity to one another, the hypercompression actually can facilitatefurther degradation which results in a reduction in the potency of theproduct as well as a less stable product with a shorter shelf life.

Current pharmaceutical regulations exist in the United States and inEurope that limit the amount of substances in pharmaceuticals which arerelated to the active pharmaceutical ingredient to no more than 1.0 wt %or 5 μg TDI (total daily intake) whichever is lower. for a maximum dailydose of 1.0 mg. These related substances have been detected in radiationsterilized polymer or copolymer containing pharmaceuticals at levelsthat make the products unusable for therapeutic purposes.

It has been found that when a hypercompressed dexamethasone/PLGA productis sterilized by gamma-irradiation, the results show that the level ofradiation induced degradation byproducts are relatively high (2.35% whenacid terminated PLGA was used and 2.16% when ester-capped PLGA wasused). When electron beam irradiation for sterilization is used withester capped PLGA, the radiation induced degradation byproduct wassubstantially reduced (between 0.89% to 1.03%).

The present invention is based on the discovery that the use of anelectron beam sterilization technique avoids the degradation problemsthat arise with gamma radiation sterilization of hypercompressedpharmaceutical controlled release products made with ester cappedlactide polymers, ester capped glycolactide polymers or ester cappedlactide-glycolactide copolymers.

SUMMARY OF THE INVENTION

The present invention provides a sterile pharmaceutical dosage formwhich comprises an ester capped lactide polymer, an ester cappedglycolide polymer or an ester capped lactide-glycolide copolymerhypercompressed with an active pharmaceutical ingredient wherein saidsterile pharmaceutical dosage form has been sterilized with an electronbeam.

The present invention also includes a method of preparing a sterilehypercompressed pharmaceutical dosage form of an ester capped lactidepolymer, an ester capped glycolide polymer or an ester cappedlactide-glycolide copolymer which comprises:

(a) combining an active pharmaceutical ingredient with an ester cappedlactide polymer, an ester capped glycolide polymer or an ester cappedlactide-glycolide copolymer to form a powdered product;

(b) compressing the powdered product of step (a) to form ahypercompresed dosage form; and

(c) exposing the hypercompressed dosage form of step (b) to asterilizing amount of an E-beam radiation source to form a sterilizedproduct.

The method of the invention allows for the use of room temperatureduring sterilization of a polypeptide or protein API in ahypercompressed controlled release ester capped lactide polymer, estercapped glycolide polymer or ester capped lactide-glycolide copolymerpharmaceutical formulation by the use of electron beam sterilization.

Accordingly, it is an object of the invention to provide novel sterilepharmaceutical formulations which comprise a polypeptide or protein APIin a sterile hypercompressed controlled release ester capped lactidepolymer or ester capped glycolide polymer or ester cappedlactide-glycolide copolymer pharmaceutical formulations.

It is also an object of the invention to provide a method for thesterilization of a polymeric material comprising an ester capped lactidepolymer, an ester capped glycolactide or an ester cappedlactide-glycolactide copolymer and/or a polypeptide or protein API in ahypercompressed controlled release lactide polymer or glycolide polymeror a lactide-glycolide copolymer pharmaceutical formulation.

It is a further object of the invention to provide a method ofadministering a sterile ophthalmic therapeutic agent which comprises apolypeptide or protein API in a hypercompressed ophthalmic insert of anester capped lactide polymer, an ester capped glycolactide polymer or anester capped lactide-glycolactide copolymer where the ophthalmictherapeutic agent is in the form of microparticles or nanoparticles.

DETAILED DESCRIPTION OF THE INVENTION

Biodegradable polymers, such as poly(L-lactide) (PLLA) andpoly(lactide-co-glycolide) (PLGA), have been utilized in biomedical andpharmaceutical applications. They have been formulated as nanoparticles,microparticles, injectable depots, films, scaffolds, and as a bulkimplant for drug delivery, due to their excellent toxicological profileand tunable biodegradability. These controlled drug delivery systems aregaining practical importance because they improve treatment and patientcompliance, provide optimized drug concentration on site over prolongperiods, and reduce undesired side effects of the drug.

Drug delivery devices formulated from PLGA and PLA and other polymershave been studied for treating diseases of the eye as well as otherareas, their hydrolytic degradation, drug release profiles, andmechanical integrity are optimized to suit various applications.

The present invention utilizes an ester capped lactide polymer, an estercapped glycolide polymer or an ester capped lactide-glycolactidecopolymer.

PLGA synthesis can be performed by: (i) a direct polycondensationbetween lactic acid and glycolic acid monomers leading to a copolymer oflower molecular weight,^(1,2) or (ii) an opening polymerization ofcyclic dimers of lactic acid and glycolic acid leading to a copolymer ofhigher molecular weight.^(3,4,5,6) The typical reaction condition ofthis type of bulk polymerization is at a temperature in the range of175° C. in the presence of an initiator such as lauryl alcohol for 2 to6 hours. Ester-capped PLGA is more stable than acid-capped PLGA as shownby their greater resistant to degradation.^(8,9)

The ester capped polymers may be prepared by esterification ortransesterification of PLA (polylactic acid), PGY (polyglycolic acid),PGLA polymers or copolymers using polycaprolactone. The ester cappedpolymers are commercially available or they may be prepared according towell know procedures. Gamma and electron-beam irradiation are among themost popular and well established processes for sterilizing polymerbased medical devices. It has been long known, however, that thesetechniques can lead to significant alterations in the materials beingtreated. High-energy radiation produces ionization and free radicals inpolymer molecules. These energy-rich species undergo dissociation,abstraction, and addition reactions in sequence leading to chemicalinstability. The destabilization process, which can occur during,immediately after, or even days, weeks, or months after irradiation,often results in physical and chemical cross-linking or chain scission.Resultant physical changes include embrittlement, discoloration, odorgeneration, stiffening, softening, enhancement or reduction of chemicalresistance, and an increase or decrease in melt temperature.

Gamma irradiation causes the radiolytic degradation of an API whichcomprise a polypeptide or a protein. This produces changes in thebiological properties of these materials by modification or destructionof the molecular configuration of the peptide or protein. The extent towhich the materials are affected depends on the surface dose delivered.By control of the electron beam energy, the penetration depth of thebeam in the hypercompressed dosage form can be manipulated; lowerenergies produce a shallower penetration depth and therefore avoidmodification or destruction of the molecular configuration of thepeptide or protein.

Electron beam (E-beam) processing or electron involves using high energyelectrons to treat an object for a variety of purposes. This may takeplace under elevated temperatures and nitrogen atmosphere. Uses forE-beam processing includes sterilization and to cross-link polymers.

The principle of electron beam technology is similar to that of atelevision set cathode ray tube. The E-beam accelerator creates a beamof electrons approximately 4 inches in diameter and energizes it to nearlight speed. The beam passes through a scan chamber where a powerfulelectro-magnetic system scans it back and forth at 200 Hz, creating acurtain of electrons about 4 feet high. A high-speed conveyor carriestotes or loaded cartons containing products to be sterilized by theE-beam, where an accurate predetermined dose of radiation is deliveredto the product.

Electron energies typically vary from the keV to MeV range, depending onthe depth of penetration required. The irradiation dose is usuallymeasured in KiloGray (kGy). NUTEK Corporation has a DualBeamconfiguration system (see below) whereby product is exposed to twoE-beam (10 MeV, 8 KW) accelerators on opposing sides of conveyors as thesamples travel through E-beam bunker on a Tote carrier.

The basic components of a typical electron beam processing device are:An electron gun (consisting of a cathode, grid, and anode) is used togenerate and accelerate the primary beam. A magnetic optical (focusingand deflection) system is used for controlling the way in which theelectron beam impinges on the material being processed (the“workpiece”). In operation, the gun cathode is the source ofthermally-emitted electrons that are both accelerated and shaped into acollimated beam by the electrostatic field geometry established by thegun electrode (grid and anode) configuration used. The electron beamthen emerges from the gun assembly through an exit hole in theground-plane anode with an energy equal to the value of the negativehigh voltage (gun operating voltage) being applied to the cathode. Thisuse of a direct high voltage to produce a high energy electron beamallows the conversion of input ac power to beam power at greater than95% efficiency, making electron beam material processing a highlyenergy-efficient technique. After exiting the gun, the beam passesthrough an electromagnetic lens and deflection coil system. The lens isused for producing either a focused or defocused beam spot on theworkpiece, while the deflection coil is used to either position the beamspot on a stationary location or provide some form of oscillatorymotion.

Electron beam processing involves irradiation (treatment) of productsusing a high-energy electron beam accelerator. Electron beamaccelerators utilize an on-off technology, with a common design beingsimilar to that of a cathode ray television.

It has been unexpectedly found that electron beam radiation can beutilized to sterilize hypercompressed pharmaceutical compositionswithout degrading ester capped lactide polymers, ester cappedglycolactide polymers or ester capped lactide-glycolactide copolymers tothe extent that such polymers will become unusable in pharmaceuticalformulations due to the generation of an unacceptable level ofdegradation products.

However, one factor working against a constant rate of drug release fromPLGA and PLLA is that they undergo bulk degradation. The bulkdegradation of these polymers is not a predictable phenomenon.

The hypercompressed devices of the invention may comprise an estercapped lactide polymer, an ester capped glycolide polymer or an estercapped lactide-glycolide copolymer that is combined with an API andhypercompressed to form a controlled release dispensing unit. The APIthat may be mixed with the polymer may comprise hydrophilic orpreferably, hydrophobic drugs that are antifungal, antibacterial,antibiotic, anti-inflammatory, immunosuppressive, tissue growth factors,dentinal desensitizers, antioxidants, nutritional agents, vitamins, odormasking agents for example. Specific examples include steroids,non-steroidal anti-inflammatory drugs, antihistamines, antibiotics,mydriatics, beta-adrenergic antagonists, anesthetics, alpha-2-betaadrenergic agonists, mast cell stabilizers, prostaglandin analogues,sympathomimetics, parasympathomimetics, antiproliferative agents, agentsto reduce angiogenesis and neovascularization, vasoconstrictors andcombinations thereof and any other agents designed to treat disease suchas an anti-neoplastic agents such as bevacizumab, ranibizumab,polynucleotide, or peptides or proteins including recombinant proteinanalogs, an angiogenic inhibitor such as Endostatin, or thalidomide;5-fluorouracil, paclitaxel, minocycline, timolol hemihydrate, rhHGH,bleomycin, ganciclovir, huperzine, tamoxifen, piroxicam,levonorgesterel, cyclosporin and the like.

Other agents include but are not limited to particular steroids butinclude steroids such as prednisone, methylprednisolone, dexamethasone;antibiotics including neomycin, tobramycin, aminoglycosides,fluoroquinolones, polymyxin, sulfacetamide, agents such as pilocarpine,isopilocarpine, physostigmine, demecarium, ecothiphate and acetylcholine and salts thereof; mydriatics and cycloplegics including agentssuch as atropine, phenylephrine, hydroxyamphetamine, cyclopentolate,homatropine, scopolamine, tropicamide and salts thereof; anestheticsinclude, lidocaine, proparacaine, tetracaine, phenacaine, and the like;beta-blockers such as timolol, carteolol, betaxolol, nadolol,levobunolol, carbonic anhydrase inhibitors such as dorzolamide,acetozolamide, prostaglandin analogues such as latanoprost, unoprostone,bimatoprost or travoprost; recombinant proteins including: Factor VIII,insulin erythropoetin, vascular endothelial growth factor, fibroblastgrowth factor, lucocerebrosidase; antibodies for therapy including:abciximab, bevacizumab, pritumumab, ocrelizumab, infliximab andsarilumab; immunotoxins including: denileukin difititox, moxetumomabpasudotox, LMB-2, oportuzumab monatox, HuM195-gelonin, A-dmDT390 andbisFv(UCHT1); cytokines including granulocyte colony stimulating factor,interferon, tumor necrosis factor, interleukin and transformation growthfactor-beta; ECM proteins including: elastin, collagen, fibronectin andpikachurin.

Generally a peptide or protein will have a weight average molecularweight of from about 5,000 to 250,000.

Prior to hypercompression, a lactide polymer, a glycolide polymer or alactide-glycolactide polymer or copolymer and an active pharmaceuticalmay be formed into microparticles known as microspheres or microcapsuleswhich are typically in the size range of about 2 microns to about 50microns, preferably from about 2 to about 25 microns and more preferablyfrom about 5 to about 20 microns in diameter. The term microsphere isused to describe a substantially homogeneous structure that is obtainedby mixing an active drug with suitable solvents and polymers so that thefinished product comprises a drug dispersed evenly in a polymer matrixwhich is shaped as a microsphere. Depending on the selected size rangeof the microparticles the term nanoparticle is used to describestructures sized from 1 to 1000 nanometers. A nanometer (nm) is onebillionth of a meter or about the size of 10 hydrogen atoms. Currently,nanoparticle drug carriers, i.e. the polymeric materialmainly consist ofsolid biodegradable particles ranging from 50-500 nm in size. Generallya particle size should be selected so that the particles may be easilymeasured and transferred as necessary for the purpose of placing theparticle in a suitable press for the application of hyper-compressiveforces to form the compressed dosage form.

Nanoparticles may be formed, for example, by sonicating a solution ofpolylactide polymer in chloroform containing a 2% w/w solution ofpolyvinyl alcohol in the presence of a therapeutic agent such as anophthalmic therapeutic agent for up to 10 minutes, using anultasonicator (Misonix XL-2020 at 50-55 W power output. Thereafter, theemulsion is stirred overnight at 4° C. to evaporate the chloroform andobtain nanoparticles of the polymer and the therapeutic agent. Themedicated nanoparticles can easily access the interior of a living celland afford the unusual opportunity of enhancing local drug therapy.

Microcapsules may also be used to form the compressed dosage forms ofthe invention. The term microcapsule is used to describe a dosage form,which is preferably nonspherical and has a polymer shell disposed arounda core that contains the active drug and any added excipient which is inthe size range set forth above. Generally microcapsules may be made byusing one of the following techniques:

(1) phase separation methods including aqueous and organic phaseseparation processes, melt dispersion and spray drying;

(2) interfacial reactions including interfacial polymerization, in situpolymerization and chemical vapor depositions;

(3) physical methods, including fluidized bed spray coating;electrostatic coating and physical vapor deposition; and

(4) solvent evaporation methods or using emulsions with an anti-solvent.

In general, the microparticles are comprised of from about 0.00001 toabout 50 parts by weight of therapeutic agent and is further comprisedof from about 50 to about 99.9 parts by weight of polymer per 100 partsby weight of the total weight of therapeutic agent and polymer. Thepreferred ranges are from 1 to 50, 5 to 40, and 20 to 30 parts by weightof therapeutic agent, the balance comprised of polymer. If desired, from1 to 5 wt % of a binder, such as polyvinyl pyrrolidone, may behomogeneously mixed with the microparticles prior to the compressionstep.

The amount of drug that is present in an implanted hypercompresseddosage form may vary but generally from 0.5-20% of the usual oral orintravenous dose of the drug may be employed but may vary substantiallydepending on the solubility, the area of implantation, the patient andthe condition to be treated. Microspheres may be formed by a typicalin-emulsion-solvent-evaporation technique as described herein.

In order to provide a biodegradable polymeric matrix for a controlledrelease dosage form which is suitable for placement in a position wherea therapeutic agent may be released for treatment of a pathology, thepolymer may be selected from ester capped poly(l-lactide),poly(dl-lactide), polyglycolide, poly(glycolide-co-lactide),poly(glycolide-co-dl-lactide), a block polymer of polyglycolide,trimethylene carbonate and polyethylene oxide, or a mixture of any ofthe foregoing. The synthetic polymer may be a polylactide or apoly(lactide-co-glycolide) with any MW (weight average) or MWpolydispersity, all ratios between lactic acid (LA) and glycolic acid(GA), and all degrees of crystallinity. Generally, the MW ranges fromabout 500 to about 10,000,000 Da, preferably from about 2,000 to about1,000,000 Da, and more preferably from about 500 to about 5,000 Da. Thep(LGA) with the ratio of LA:GA at about 75:25 to about 85:15 (mol:mol)and the MW from about 5,000 to about 500,000 may be used. Thelactide/glycolide polymers are bulk-eroding polymers (not surfaceeroding polymers) and the polymer will hydrolyze when formed into amicroparticle matrix as water enters the matrix and the polymerdecreases in molecular weight. It is possible to shift the resorptioncurves to longer times by increasing the polymer molecular weight, usingL-polymers and decreasing the surface area by increasing the size of themicroparticles or the size of the dosage form. The lactide/glycolidecopolymers are available with inherent viscosities as high as 6.5 dl/gand as low as 0.15 dl/g. The lower molecular weight copolymers arepreferred for the present invention. It has been found that a mol ratioof 50:50 of glycolide to lactide results in the most rapid degradationand the corresponding release of drug. By increasing the ratio oflactide in the polymer backbone from about 50 mole % to 100% the rate ofrelease can be reduced to provide an extended therapeutic effect from asingle dosage unit.

A preferred encapsulating polymer is poly(glycolide-co-dl-lactide)capped with an ester that may be formed with a straight or branchedchain aliphatic alcohol or by other means. The ester capped polymericmaterial which serves as a preferred controlled release delivery systemfor the dispensing device is similar in structure to the absorbablepolyglycolic acid and polyglycolic/polylactic acid suture materials. Thepolymeric carrier serves as a sustained-release delivery system for thetherapeutic agents. The polymers undergo biodegradation through aprocess whereby their ester bonds are hydrolyzed to form normalmetabolic compounds, lactic acid and glycolic acid and allow for releaseof the therapeutic agent.

Copolymers consisting of various ratios of lactic and glycolic acidshave been studied for differences in rates of degradation. It is knownthat the biodegradation rate depends on the ratio of lactic acid toglycolic acid in the copolymer, and the 50:50 copolymer degrades mostrapidly. The selection of a biodegradable polymer system avoids thenecessity of removing an exhausted non-biodegradable structure from theeye with the accompanying trauma.

The ester capping of the lactic and glycolic polymers orlactide-glycolide copolymers does not substantially affect the releaserates of drugs formulated in these copolymers as compared with lacticacid and glycolic acid copolymers that are not ester capped.

After the microspheres are prepared, they are compressed at very highforces to form the dispensing device of the invention. Thehyper-compression may be carried out in an apparatus that is capable orpermits the application of from 50,000 to 350,000 psi (hereafter K isused in place of 1,000) pressure to microparticles or nanoparticles, orfrom 100 Kpsi to 300 Kpsi or 200 Kpsi to 300 Kpsi or 50 or 60 Kpsi to160 or 170 Kpsi or especially 60 Kpsi to 170 Kpsi. The term psi (poundsper square inch) is determined by taking the force in pounds that isapplied to the particular dosage form and measuring or calculating thearea of the top of the dosage form or die in square inches so that aconversion may be made to express the pressure applied to the dosageform in psi.

The hyper-compressed dispensing device may be a perfect spheroid, butpreferably a distorted spheroid such as a flat disc, rod, pellet withrounded or smooth edges that is small enough to be placed under the skinin a location such as bones and their joints, including the knuckles,toes, knees, hips and shoulders; glands, e.g. pituitary, thyroid,prostate, ovary or pancreas, or organs, e.g. liver, brain, heart, andkidney. More particularly, the dispensing device of the invention may beutilized to treat pathology by implanting the device at or near the siteof the pathology, or in a way that will affect the pathology, such asany part that comprises the body of a human or animal or fish or otherliving species. Such parts may include the contents of a cell, any partof the head, neck, back, thorax, abdomen, perineum, upper or lowerextremities. Any part of the osteology including but not limited to thevertebral column, the skull, the thorax, including the sternum or ribs,the facial bones, the bones of the upper extremity, such as theclavicle, scapula or humerus; the bones of the hand, such as the carpus;the bones of the lower extremity, such as the ilium or the femur; thefoot, such as the tarsus; joints or ligaments; muscles and fasciae; thecardiovascular system, such as the heart, the arteries, the veins, orthe capillaries or blood; the lymphatic system, such as the thoracicduct, thymus or spleen; the central or peripheral nervous system, thesensory organs, such as eye, ear, nose; the skin; the respiratorysystem, such as the lungs, the larynx, the trachea and bronchi; thedigestive system, such as the esophagus, the stomach or the liver; theurogenital system, such as the urinary bladder, the prostate, or theovary; the endocrine glands, such as the thyroid, the parathyroid or theadrenals.

A recombinant humanized monoclonal IgGl antibody that binds to andinhibits the biologic activity of human vascular endothelial growthfactor (VEGF) and is a recognized agent for the treatment of age relatedmacular degeneration (AMD). Bevacizumab contains human framework regionsand the complementarity-determining regions of a murine antibody thatbinds to VEGF. Bevacizumab is produced in a Chinese Hamster Ovarymammalian cell expression system in a nutrient medium containing theantibiotic gentamicin and has a molecular weight of approximately 149kilodaltons.

EXAMPLE 1

A preparation of hypercompressed PLGA/Dexamethasone particles preparedfrom an acid terminated PLGA (Purasorb PDLG5002 having an inherentviscosity of 0.16-0.24 dl/g. in chloroform at 25° C., 1.0 g/dl and a50:50 wt. ratio of lactide to glycolide) by dissolving the PLGA inmethylene chloride to make a PLGA/MeCl₂ solution a total of 5 ml with0.23 wt % of dexamethasone. The solvent was evaporated and 250.12 mg ofthe particles were compressed in a 7.87 mm diameter die using a pressureof 200 Kpsi to form a pellet weighing 242.14 mg having a thickness of3.76 mm. The pellet thus obtained was irradiated with γ-ray (a total of25 kGy, as a single dose) and the formulation was analyzed by HPLC, theresults show the presence of up to 2.35 wt % dexamethasone RS and 0.37wt % RS without any radiation as set forth in the Table.

A preparation of hypercompressed PLGA containing 0.23 wt % dexamethasoneparticles was prepared from ester capped PLGA (Resomer RG755S having aninherent viscosity of 0.5-0.7 dl/g. in 0.1 wt % in chloroform at 25° C.and a 75:25 wt. ratio of lactide to glycolide) was prepared in the samemanner that the PLGA acid terminated (Purasorb 5022) formulation wasprepared. This preparation was irradiated with e-beam radiation (a totalof 25 kGy, as two equal doses of 12½ kGy) and the formulation wasanalyzed by HPLC. The results show the presence of two majordexamethasone RS materials (0.33% and 0.56%, respectively). Likewise,the same preparation was irradiated with e-beam (a total of 25 kGy, as asingle dose) and the formulation was analyzed by HPLC, the results showthe presence of three major Dexamethasone RS (0.1%, 0.36% and 0.57%,respectively). The same hypercompressed PLGA/Dexamethasone particlesthat were prepared from the same ester capped PLGA (Resomer RG755S)shows the presence of 2.16% dexamethasone RS after γ-irradiation and 0.4wt % RS without any radiation as set forth in the Table.

The hypercompressed particles were sterilized by either γ-irradiation ore-beam, the API Dexamethasone was used as a control. The results aresummarized in the Table below.

TABLE % Related Substances (RS) Dexameth- Dexameth- Dose asone/PLGAasone/PLGA Irradi- (kGy) × Dexameth- (Acid capped (Ester capped ationpass asone PLGA) PLGA) None N/A 0.23% 0.37% 0.4%  γ 25 × 1 0.52% 2.35%2.16% e-Beam 12½ × 2 0.23% N/A 0.33% (0.90 RRT) (1.26 RRT) 0.56% (1.26RRT) Σ 0.89% e-Beam 25 × 1 0.22% N/A 0.36% (0.90 RRT) (1.26 RRT) 0.57%(1.26 RRT)  0.1% (1.30 RRT) Σ 1.03%

FDA Guidance for Industry Q3B(R2) Impurities in New Drug Products andEuropean Medicine Agency Note for Guidance on Impurities in New DrugProducts (CPMP/ICH/2738/99) state that the qualification threshold fordegradation products (i.e., RS) in new drug products, “1.0% or 5 μg TDI(Total Daily Intake), whichever is lower, for a maximum daily dose: <1mg”. Since the hypercompressed microparticles are a controlled releasesystem designed specifically for highly focal and prolonged release ofdrugs in very small doses, the amount of drug release daily is expectedto be well within the <100 μg range (substantially lower than that ofthe maximum allowable dose of <1 mg daily stated in the officialguidance; thus, the above data indicate that the levels of identifiableRS (and the unidentified RS) are expected to be substantially less thanthe 5 maximum tolerable TDI dose allowed. Further qualification of RSare deemed unnecessary.

For gamma sterilization, the parameters were as follows:

-   -   Specified dose: 22.5 kGy to 27.5 kGy (i.e., 25 kGy±10%)    -   Delivered dose: 24.2 kGy to 25.8 kGy    -   Exposure time: 299 minutes

E-beam irradiation was performed at doses of 12.5 KGy and 25 KGy in anelectron-beam accelerator at an accelerating voltage of kV, at roomtemperature, humidity, and without the presence of oxygen in a nitrogenatmosphere. These radiation doses were chosen because previous studieshad shown that polymers irradiated at these doses exhibited a moderate(5 Mrad) to substantial (20 Mrad) increase in their degradation rateswhich would give rise to pseudo surface degradation from 20-5 to 0 Mradmulti-layer film constructs.

The invention claimed is:
 1. A sterile pharmaceutical dosage form whichcomprises an ester capped lactide polymer, ester capped glycolidepolymer or an ester capped lactide-glycolide copolymer that ishypercompressed with an active pharmaceutical ingredient wherein saidsterile pharmaceutical dosage form has been sterilized with an electronbeam.
 2. A sterile pharmaceutical dosage form as defined in claim 1where the active pharmaceutical ingredient is selected from the groupconsisting of steroids, non-steroidal anti-inflammatory drugs,antihistamines, antibiotics, mydriatics, beta-adrenergic antagonistsanesthetics,alpha-2-beta adrenergic agonists, mast cell stabilizers,prostaglandin analogues, sympathomimetics, parasympathomimetics,antiproliferative agents, agents to reduce ocular angiogenesis andneovascularization, vasoconstrictors, anti-neoplastic agents, apolynucleotide, or a recombinant protein analog an angiogenic inhibitorsand combinations thereof.
 3. A sterile pharmaceutical dosage form asdefined in claim 2 where the therapeutic agent is a steroid.
 4. Asterile pharmaceutical dosage form as defined in claim 1 where thepolymer is selected from the group consisting of ester cappedpoly(dl-lactide), ester capped polyglycolide,ester cappedpoly(glycolide-co-lactide), and ester cappedpoly(glycolide-co-dl-lactide), or a mixture of any of the foregoing. 5.A sterile pharmaceutical dosage form as defined in claim 4 where thedosage form has been compressed by the application of 50K psi to 350Kpsi.
 6. A sterile pharmaceutical dosage form as defined in claim 5 wherethe dosage form has been compressed by the application of 100 Kpsi to300 Kpsi.
 7. A sterile pharmaceutical dosage form as defined in claim 5where the dosage form has been compressed by the application of 200 Kpsito 300 Kpsi.
 8. A method of preparing a sterile hypercompressedpharmaceutical dosage form according to claim 1 where the activepharmaceutical ingredient is selected from the group consisting ofpeptides and proteins.
 9. A method of preparing a sterilehypercompressed pharmaceutical dosage form of an ester capped lactidepolymer, ester capped glycolide polymer or an ester cappedlactide-glycolide copolymer which comprises: (a) combining an activepharmaceutical ingredient with an ester capped lactide polymer, an estercapped glycolide polymer or an ester capped lactide-glycolide copolymerto form a powdered product; (b) hypercompressing the powdered product ofstep (a) to form a hypercompresed dosage form; and (c) exposing thehypercompressed dosage form of step (b) to a sterilizing amount of anE-beam radiation source to form a sterilized product.
 10. A method ofpreparing a sterile hypercompressed pharmaceutical dosage form accordingto claim 9 where the active pharmaceutical ingredient is selected fromthe group consisting of steroids, non-steroidal anti-inflammatory drugs,antihistamines, antibiotics, mydriatics, beta-adrenergic antagonistsanesthetics, alpha-2-beta adrenergic agonists, mast cell stabilizers,prostaglandin analogues, sympathomimetics, parasympathomimetics,antiproliferative agents, agents to reduce ocular angiogenesis andneovascularization, vasoconstrictors, anti-neoplastic agents, apolynucleotide, or a recombinant protein analog an angiogenic inhibitorsand combinations thereof.
 11. A method of preparing a sterilehypercompressed pharmaceutical dosage form according to claim 9 wherethe dosage form has been compressed by the application of 50K psi to350K psi.
 12. A method of preparing a sterile hypercompressedpharmaceutical dosage form according to claim 9 where the dosage formhas been compressed by the application of 100 Kpsi to 300 Kpsi.
 13. Amethod of preparing a sterile hypercompressed pharmaceutical dosage formaccording to claim 9 where the dosage form has been compressed by theapplication of 200 Kpsi to 300 Kpsi.